Momelotinib therapy for myelofibrosis: a 7-year follow-up

Abstract

One-hundred Mayo Clinic patients with high/intermediate-risk myelofibrosis (MF) received momelotinib (MMB; JAK1/2 inhibitor) between 2009 and 2010, as part of a phase 1/2 trial (NCT00935987); 73% harbored JAK2 mutations, 16% CALR, 7% MPL, 44% ASXL1, and 18% SRSF2. As of July 2017, MMB was discontinued in 91% of the patients, after a median treatment duration of 1.4 years. Grade 3/4 toxicity included thrombocytopenia (34%) and liver/pancreatic test abnormalities (<10%); grade 1/2 peripheral neuropathy occurred in 47%. Clinical improvement (CI) occurred in 57% of patients, including 44% anemia and 43% spleen response. CI was more likely to occur in ASXL1-unmutated patients (66% vs 44%) and in those with <2% circulating blasts (66% vs 42%). Response was more durable in the presence of CALR type 1/like and absence of very high-risk karyotype. In multivariable analysis, absence of CALR type 1/like (HR 3.0; 95% CI 1.2–7.6) and presence of ASXL1 (HR 1.9; 95% CI 1.1–3.2) or SRSF2 (HR 2.4, 95% CI 1.3–4.5) mutations adversely affected survival. SRSF2 mutations (HR 4.7, 95% CI 1.3–16.9), very high-risk karyotype (HR 7.9, 95% CI 1.9–32.1), and circulating blasts ≥2% (HR 3.9, 95% CI 1.4–11.0) predicted leukemic transformation. Post-MMB survival (median 3.2 years) was not significantly different than that of a risk-matched MF cohort not receiving MMB.

The Myeloproliferative Neoplasm Landscape: A Patient’s Eye View

“…Firstly, momelotinib, a JAK1/JAK2 inhibitor, showed similar responses to ruxolitinib with respect to reduction in spleen size, but lesser alleviation of constitutional symptoms in phase 3 trials in patients with MF, although momelotinib was associated with a reduced transfusion requirement relative to ruxolitinib [53,54]. Long-term data failed to show a survival benefit of treatment with momelotinib, and demonstrated a high incidence of peripheral neuropathy [55], and studies of momelotinib in PV and ET were discontinued as a result of limited efficacy [56]. However, the FDA has recently granted fast-track designation to momelotinib for the treatment of patients with intermediate-or high-risk MF who previously received a JAK inhibitor, and a phase 3 trial to evaluate the activity of momelotinib for symptomatic, anaemic patients with MF previously treated with JAK inhibitor therapy is planned [57].…”

Primary myelofibrosis: 2019 update on diagnosis, risk‐stratification and management

“…Genetic markers in PMF have also proven to be the primary determinants of survival and are now part of formal prognostic systems, such as MIPSS70+ version 2.0 and GIPSS; in this regard, ASXL1 and SRSF2 mutations and unfavorable karyotype have consistently been associated with inferior survival. There is also emerging evidence for genetic prediction of treatment response; in one clinical trial using the JAK2 inhibitor momelotinib, for example, patients with ASXL1 mutations were less likely to respond while those with CALR type 1/like mutations displayed durable response . In another study of the telomerase inhibitor imetelstat, treatment response was more likely in patients with SF3B1 or U2AF1 mutations and less likely in those with ASXL1 mutations .…”

<p>Beyond Ruxolitinib: Fedratinib and Other Emergent Treatment Options for Myelofibrosis</p>

“…46,47 Adverse event profiles were comparable for momelotinib, ruxolitinib, and BAT with peripheral neuropathy (in up to 50% of patients) and myelosuppression being the most frequent adverse events seen with momelotinib. 46,48,49 In single-arm studies of mostly treatment-naïve patients, momelotinib achieved clinical/symptom responses in up to 57.6% and spleen responses in 45% of patients, respectively, and no survival benefit compared to risk-matched patients not receiving momelotinib was seen. [48][49][50] However, momelotinib unexpectedly improved anemia in patients with myelofibrosis, which can be a dose-or even treatment-limiting side effect with other JAK inhibitors.…”

“…46,48,49 In single-arm studies of mostly treatment-naïve patients, momelotinib achieved clinical/symptom responses in up to 57.6% and spleen responses in 45% of patients, respectively, and no survival benefit compared to risk-matched patients not receiving momelotinib was seen. [48][49][50] However, momelotinib unexpectedly improved anemia in patients with myelofibrosis, which can be a dose-or even treatment-limiting side effect with other JAK inhibitors. 46,47 In the SIMPLIFY-1 and -2 trials, rates of RBC transfusion independence were higher with momelotinib in both treatment-naïve and ruxolitinibpretreated patients.…”